Clinical status and perspective on the application of immunotherapy combined with chemotherapy in advanced non-small cell lung cancer: a review.

The therapeutic landscape of advanced non-small cell lung cancer (NSCLC) has been significantly improved by developing immunotherapy represented by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors (ICI). Furthermore, immunotherapy combined with chemotherapy is an essential treatment strategy for driver-negative advanced NSCLC, especially in a population with PD-L1 <50%, and leads to long-term survival in the entire population regardless of the PD-L1 expression status. However, specific challenges must be overcome, including how to use immunotherapy with chemotherapy in clinics. Furthermore, the application of immunotherapy with chemotherapy in populations such as elderly patients and patients with brain metastases, oligometastases, epidermal growth factor receptor (EGFR) gene mutation, anaplastic lymphoma kinase (ALK) gene rearrangements, and other driver gene-positive populations must be further explored. The biomarkers associated with immunotherapy and chemotherapy are still unclear, and the search for predictive biomarkers can contribute toward more precise and personalized immunotherapy. Furthermore, treatment strategies after immunotherapy and chemotherapy resistance are of significant focus clinically, and clinical studies with multiple combination therapy strategies are ongoing. Therefore, based on the reported status of immunotherapy combined with chemotherapy for advanced NSCLC, this study conducted a comprehensive literature review by searching keywords "PD-1 and PD-L1, immune checkpoint inhibitor (ICI), and NSCLC" in MEDLINE, major conferences, and major clinical research projects to elucidate the therapeutic efficacy of immunotherapy combined with chemotherapy as the current first-line treatment approach for various types of NSCLC patients. Additionally, it addresses several pressing challenges associated with immunotherapy combined with chemotherapy, including enhancing treatment response and survival rate in specific patient populations and identifying potential biomarkers.

Layer-by-layer assembly of homopolypeptide polyelectrolytes on asymmetric nanochannels for the detection of nickel ions.

Nickel stands out as one of the prevalent heavy metal ionic pollutants found in water. It is urgent to devise a simple, efficient, budget-friendly, highly-selective and proficient method for detecting Ni(II). This work reports an approach to design a nanofluidic diode for the ultrasensitive and label-free detection of nickel ions based on layer-by-layer assembly of polyarginine (PA) and polyglutamic acid (γ-PGA) on the inner surface of asymmetric nanochannels. We can tune the adsorption/desorption characteristics of the asymmetric nanochannels for Ni2+ by adjusting the pH changes, i.e., the PA-γ-PGA modified nanochannels adsorb Ni2+ at pH 6 and desorb at pH 3 in aqueous solution. This pivotal adjustment facilitates the reusable and specific detection of nickel ions with a detection limit of 1 × 10-8 M. Moreover, the system demonstrates commendable stability and recyclability, enhancing its practical applicability. This innovative system holds promise for recognizing and detecting nickel ions in diverse environments such as water, blood, and cells. The robust performance and adaptability of our proposed system instill confidence in its potential for future applications.

Influence of dissolved organic matter with different molecular weight from chicken manure on ferrihydrite adsorption and re-release of antimony(V).

Applying organic fertilizer is the main way to enhance soil fertility through the interfacial reaction between mineral and dissolved organic matter (DOM). However, the interfacial reaction between minerals and DOM may influence antimony(V) (Sb(V)) mobility in agricultural soils around antimony mines. In our study the ferrihydrite (Fh) was chosen as a representative mineral, to reveal the effect of its interaction with chicken manure organic fertilizer (CM-DOM) with Fh on Sb(V) migration. In this study, we investigated different organic matter molecular weights and C/Fe molar ratios. Our findings indicated that the addition of CM-DOM decreased the adsorption of Sb(V) by Fh and promoted the re-release of Sb(V) adsorbed on Fh. This effect was enhanced by increasing the C/Fe molar ratio. Fh mainly affects its interaction with Sb(V) through electrostatic gravitational interaction and ligand exchange, but the presence of CM-DOM weakens the electrostatic interaction between Fh and Sb(V) as well as competes with Sb(V) for the hydroxyl reactive site on Fh surface. In addition, the smaller molecular weight fraction (<10 kDa) of CM-DOM has higher aromaticity and hydrophobicity, which potentially leads to more intense competition with Sb(V) for the reaction sites on Fh. Therefore, the application of organic fertilizer may promote Sb(V) migration, posing significant risks to soil ecosystems and human health, which should be a concern in field soil cultivation.

Circadian patterns and photoperiodic modulation of clock gene expression and neuroendocrine hormone secretion in the marine teleost Larimichthys crocea.

The light/dark cycle, known as the photoperiod, plays a crucial role in influencing various physiological activities in fish, such as growth, feeding and reproduction. However, the underlying mechanisms of this influence are not fully understood. This study focuses on exploring the impact of different light regimes (LD: 12 h of light and 12 h of darkness; LL: 24 h of light and 0 h of darkness; DD: 0 h of light and 24 h of darkness) on the expression of clock genes (LcClocka, LcClockb, LcBmal, LcPer1, LcPer2) and the secretion of hormones (melatonin, GnRH, NPY) in the large yellow croaker, Larimichthys crocea. Real-time quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assays were utilized to assess how photoperiod variations affect clock gene expression and hormone secretion. The results indicate that changes in photoperiod can disrupt the rhythmic patterns of clock genes, leading to phase shifts and decreased expression. Particularly under LL conditions, the pineal LcClocka, LcBmal and LcPer1 genes lose their rhythmicity, while LcClockb and LcPer2 genes exhibit phase shifts, highlighting the importance of dark phase entrainment for maintaining rhythmicity. Additionally, altered photoperiod affects the neuroendocrine system of L. crocea. In comparison to the LD condition, LL and DD treatments showed a phase delay of GnRH secretion and an acceleration of NPY synthesis. These findings provide valuable insights into the regulatory patterns of circadian rhythms in fish and may contribute to optimizing the light environment in the L. crocea farming industry.

Artemisia capillaris Thunb. Polysaccharide alleviates cholestatic liver injury through gut microbiota modulation and Nrf2 signaling pathway activation in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: According to traditional Chinese medicine (TCM) theory, cholestasis belongs to category of jaundice. Artemisia capillaris Thunb. has been widely used for the treatment of jaundice in TCM. The polysaccharides are the one of main active components of the herb, but its effects on cholestasis remain unclear. AIM OF THE STUDY: To investigate the protective effect and mechanism of Artemisia capillaris Thunb. polysaccharide (APS) on cholestasis and liver injury. MATERIALS AND METHODS: The amelioration of APS on cholestasis was evaluated in an alpha-naphthyl isothiocyanate (ANIT)-induced mice model. Then nuclear Nrf2 knockout mice, mass spectrometry, 16s rDNA sequencing, metabolomics, and molecular biotechnology methods were used to elucidate the associated mechanisms of APS against cholestatic liver injury. RESULTS: Treatment with low and high doses of APS markedly decreased cholestatic liver injury of mice. Mechanistically, APS promoted nuclear translocation of hepatic nuclear factor erythroid 2-related factor (Nrf2), upregulated downstream bile acid (BA) efflux transporters and detoxifying enzymes expression, improved BA homeostasis, and attenuated oxidative liver injury; however, these effects were annulled in Nrf2 knock-out mice. Furthermore, APS ameliorated the microbiota dysbiosis of cholestatic mice and selectively increased short-chain fatty acid (SCFA)-producing bacteria growth. Fecal microbiota transplantation of APS also promoted hepatic Nrf2 activation, increased BA efflux transporters and detoxifying enzymes expression, ameliorated intrahepatic BA accumulation and cholestatic liver injury. Non-targeted metabolomics and in vitro microbiota culture confirmed that APS significantly increased the production of a microbiota-derived SCFA (butyric acid), which is also able to upregulate Nrf2 expression. CONCLUSIONS: These findings indicate that APS can ameliorate cholestasis by modulating gut microbiota and activating the Nrf2 pathway, representing a novel therapeutic approach for cholestatic liver disease.

An environmentally friendly strategy for reducing the environmental risks of heavy metals adsorbed by kaolinite.

Plenty of heavy metals (HMs) that are adsorbed on clay minerals (such as kaolinite), in addition to low molecular-weight organic acids (such as oxalic acid (OA)) with high activities, are widespread in the natural environment. In the present study, the effects of OA on the environmental behaviors of Pb2+/Cd2+ adsorbed by kaolinite have been investigated. The effectiveness and mechanisms of calcium silicate (CS) and magnesium silicate (MS) in reducing the environmental risks of the HMs have also been studied. The results showed that the releases of Pb2+/Cd2+ increased with an increasing concentration of OA. When different dosages of CS/MS were added to the aging system, a redistribution of HMs took place and the free form of Pb2+/Cd2+ decreased to very low levels. Also, the unextractable Pb2+/Cd2+ increased to high levels. Furthermore, a series of characterizations showed that the released HMs were re-captured by the CS/MS. In addition, the CS immobilized the OA in the solution during the aging process, which also facilitated an immobilization of the carbon element in the environment. In general, the present study has contributed to a further understanding of the transport behaviors of the HMs in natural environments, and of the interactions between CS (or MS), the environmental media, and the heavy metal contaminants. In addition, this study has also provided an eco-friendly strategy for an effective remediation of heavy metal pollution.

Effect of Pulsatilla decoction on vulvovaginal candidiasis in mice. Evidences for its mechanisms of action.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a common infection that affects the female reproductive tract. Pulsatilla decoction (PD), a traditional Chinese herbal medicine, is a classic and effective prescription for VVC. However, its mechanism of action remains unclear. PURPOSE: This study aimed to evaluate the efficacy and potential mechanism of action of the n-butanol extract of Pulsatilla decoction (BEPD) in VVC treatment. METHODS: High performance liquid chromatography (HPLC) was used to detect the main active ingredients in BEPD. A VVC-mouse model was constructed using an estrogen-dependent method to evaluate the efficacy of BEPD in VVC treatment. Fungal burden and morphology in the vaginal cavity were comprehensively assessed. Candida albicans-induced inflammation was examined in vivo and in vitro. The effects of BEPD on the Protein kinase Cδ (PKCδ) /NLR family CARD domain-containing protein 4 (NLRC4)/Interleukin-1 receptor antagonist (IL-1Ra) axis were analyzed using by immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and reverse transcription-quantitative polymerase chain reaction (qRT-PCR). RESULTS: BEPD inhibited fungal growth in the vagina of VVC mice, preserved the integrity of the vaginal mucosa, and suppressed inflammatory responses. Most importantly, BEPD activated the "silent" PKCδ/NLRC4/IL-1Ra axis and negatively regulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, thereby exerting a therapeutic efficacy on VVC. CONCLUSIONS: BEPD effects on mice with VVC were dose-dependent. BEPD protects against VVC by inhibiting inflammatory response and NLRP3 inflammasome via the activation of the PKCδ/NLRC4/IL-1Ra axis. This study revealed the pharmacological mechanism of BEPD in VVC treatment and provided further evidence for the application of BEPD in VVC treatment.

Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRß/PI3K/AKT pathway.

Introduction: Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis (CLF) and its underlying mechanisms were evaluated. Methods: A 3, 5-diethoxycarbonyl-1, 4-dihydro-collidine (DDC)-induced cholestatic mouse model was used to investigate the amelioration of YCZFD on CLF. Data-independent acquisition-based mass spectrometry was performed to investigate proteomic changes in the livers of mice in three groups: control, model, and model treated with high-dose YCZFD. The effects of YCZFD on the expression of key proteins were confirmed in mice and cell models. Results: YCZFD significantly decreased the levels of serum biochemical, liver injury, and fibrosis indicators of cholestatic mice. The proteomics indicated that 460 differentially expressed proteins (DEPs) were identified among control, model, and model treated with high-dose YCZFD groups. Enrichment analyses of these DEPs revealed that YCZFD influenced multiple pathways, including PI3K-Akt, focal adhesion, ECM-receptor interaction, glutathione metabolism, and steroid biosynthesis pathways. The expression of platelet derived growth factor receptor beta (PDGFRß), a receptor associated with the PI3K/AKT and focal adhesion pathways, was upregulated in the livers of cholestatic mice but downregulated by YCZFD. The effects of YCZFD on the expression of key proteins in the PDGFRß/PI3K/AKT pathway were further confirmed in mice and transforming growth factor-ß-induced hepatic stellate cells. We uncovered seven plant metabolites (chlorogenic acid, scoparone, isoliquiritigenin, glycyrrhetinic acid, formononetin, atractylenolide I, and benzoylaconitine) of YCZFD that may regulate PDGFRß expression. Conclusion: YCZFD substantially protects against DDC-induced CLF mainly through regulating the PDGFRß/PI3K/AKT signaling pathway.

Oxysterol 25-hydroxycholesterol activation of ferritinophagy inhibits the development of squamous intraepithelial lesion of cervix in HPV-positive patients.

Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.

Dietary change influences the composition of the fecal microbiota in two rescued wild raccoon dogs (Nyctereutes procyonoides).

The gut microbiota of wild animals, influenced by various factors including diet, nutrition, gender, and age, plays a critical role in their health and disease status. This study focuses on raccoon dogs (Nyctereutes procyonoides), a commonly found wild animal, and its gut microbiota composition in response to dietary shifts. The study aimed to compare the fecal bacterial communities and diversity of rescued raccoon dogs fed three different diet types (fish and amphibians, mixed protein with maize, and solely maize) using high-throughput sequencing. Results indicated that the dietary composition significantly influenced the gut microbiota, with notable differences in the abundance of several key phyla and genera. The study identified Firmicutes as the dominant phylum in all diet groups, with notable variations in the relative abundances of Bacteroidota, Proteobacteria, and Verrucomicrobiota. Notably, the group solely fed maize exhibited a significant increase in Proteobacteria, potentially linked to dietary fiber and lignin degradation. The genus-level analysis highlighted significant differences, with Lactobacillus and Bifidobacterium responding to dietary shifts. The genus Akkermansia in Verrucomicrobiota can be identified as a marker for assessing the health of the gut and deserves further investigation. Gender-specific differences in the gut microbiota were observed, highlighting the influence of individual variation. Furthermore, the analysis of bacterial functions suggested a connection between diet and host metabolism, emphasizing the need for further research to understand the complex mechanisms underlying the relationship between dietary composition and gut microbiota in wild animals. These findings provide crucial insights into conservation and rescue efforts for wild animals.

Physical impediment to sodium houttuyfonate conversely reinforces ß-glucan exposure stimulated innate immune response to Candida albicans.

Candida albicans is a dimorphic opportunistic pathogen in immunocompromised individuals. We have previously demonstrated that sodium houttuyfonate (SH), a derivative of medicinal herb Houttuynia cordata Thunb, was effective for antifungal purposes. However, the physical impediment of SH by C. albicans ß-glucan may weaken the antifungal activity of SH. In this study, the interactions of SH with cell wall (CW), extracellular matrix (EM), CW ß-glucan, and a commercial ß-glucan zymosan A (ZY) were inspected by XTT assay and total plate count in a standard reference C. albicans SC5314 as well as two clinical fluconazole-resistant strains Z4935 and Z5172. After treatment with SH, the content and exposure of CW ß-glucan, chitin, and mannan were detected, the fungal clearance by phagocytosis of RAW264.7 and THP-1 was examined, and the gene expressions and levels of cytokines TNF-ɑ and IL-10 were also monitored. The results showed that SH could be physically impeded by ß-glucan in CW, EM, and ZY. This impediment subsequently triggered the exposure of CW ß-glucan and chitin with mannan masked in a time-dependent manner. SH-induced ß-glucan exposure could significantly enhance the phagocytosis and inhibit the growth of C. albicans. Meanwhile, the SH-pretreated fungal cells could greatly stimulate the cytokine gene expressions and levels of TNF-ɑ and IL-10 in the macrophages. In sum, the strategy that the instant physical impediment of C. albicans CW to SH, which can induce the exposure of CW ß-glucan may be universal for C. albicans in response to physical deterrent by antifungal drugs.

Effect evaluation of different preventive measures for ileus after abdominal operation: A systematic review and network meta-analysis.

Background: Different approaches to the prevention of postoperative ileus have been evaluated in numerous randomized controlled trials. This network meta-analysis aimed to investigate the relative effectiveness of different interventions in preventing postoperative ileus. Methods: Randomized controlled trials (RCTS) on the prevention of postoperative ileus were screened from Chinese and foreign medical databases and compared. STATA software was used for network meta-analysis using the frequency method. Random-effects network meta-analysis was also used to compare all schemes directly and indirectly. Results: A total of 105 randomized controlled trials with 18,840 participants were included in this report. The results of the network meta-analysis showed that intravenous analgesia was most effective in preventing the incidence of postoperative ileus, the surface under the cumulative ranking curve (SUCRA) is 90.5. The most effective intervention for reducing the first postoperative exhaust time was postoperative abdominal mechanical massage (SUCRA: 97.3), and the most effective intervention for reducing the first postoperative defecation time was high-dose opioid antagonists (SUCRA: 84.3). Additionally, the most effective intervention for reducing the time to initiate a normal diet after surgery was accelerated rehabilitation (SUCRA: 85.4). A comprehensive analysis demonstrated the effectiveness and prominence of oral opioid antagonists and electroacupuncture (EA) combined with gum. Conclusion: This network meta-analysis determined that oral opioid antagonists and EA combined with chewing gum are the most effective treatments and optimal interventions for reducing the incidence of postoperative ileus. However, methods such as abdominal mechanical massage and coffee require further high-quality research.

The role of large mammalian herbivores in shaping and maintaining soil microbial communities of natural mineral licks: A case study on sika deer at the firebreak adjacent to the Sino-Russian border.

Mineral licks are indispensable habitats to the life history of large mammal herbivores (LMH). Geophagy at licks may provide the necessary minerals for LMH, while LMH may be ecosystem engineers of licks by altering vegetation cover and soil physicochemical properties (SPCP). However, the precise relationship between the LMH and licks remains unclear. To clarify the geophagy function of licks for LMH and their influence on soil at licks, we recorded visitation patterns of sika deer around licks and compared SPCP and microbial communities with the surrounding matrix in a firebreak adjacent to the Sino-Russian border. Our study indirectly supports the "sodium supplementation" hypothesis. Proofs included (1) a significantly higher sodium, iron, and aluminum contents than the matrix, while lower carbon, nitrogen, and moisture contents; (2) significantly higher deer visitation during sodium-demand season (growing season), along with an avoidance of licks with high iron contents, which is toxic when overdose. The microbes at the licks differed from those at the matrix, mainly driven by low soil carbon and nitrogen and altered biogeochemical cycles. The microbial communities of licks are vulnerable because of their unstable state and susceptibility to SPCP changes. Structural equation modeling (SEM) clearly showed a much stronger indirect effect of deer on microbes at licks than at the matrix, especially for bacteria. Multiple deer behaviors at licks, such as grazing, trampling, and excretion, can indirectly shape and stabilize microbes by altering carbon and nitrogen input. Our study is the first to characterize soil microbial communities at mineral licks and demonstrate the processes by which LMH shapes those communities. More studies are required to establish a general relationship between the LMH and licks to promote the conservation of natural licks for wildlife.

Effect of the Pulsatilla decoction n-butanol extract on vulvovaginal candidiasis caused by Candida glabrata and on its virulence factors.

Vulvovaginal candidiasis (VVC) caused by Candida glabrata (C. glabrata) is more persistent and resistant to treatment than when caused by Candida albicans (C. albicans) and has been on the rise in recent years. The n-butanol extract of Pulsatilla Decoction (BEPD) has been shown to be effective in treating VVC caused by C. glabrata, but the underlying mechanism of action remains unclear. In this study, the experimenter conducted in vitro and in vivo experiments to explore the effects of BEPD on the virulence factors of C. glabrata, as well as its efficacy, with a focus on possible immunological mechanism in VVC caused by C. glabrata. The contents of Anemoside B4, Epiberberine, Berberine, Aesculin, Aesculetin, Phellodendrine and Jatrorrhizine in BEPD, detected by high-performance liquid chromatography, were 31,736.64, 13,529.66, 105,143.72, 19,406.20, 4952.67, 10,317.03, 2489.93 µg/g, respectively. In vitro experiments indicated that BEPD moderately inhibited the growth of C. glabrata, its adhesion, and biofilm formation, and affected the expression of efflux transporters in the biofilm state. In vivo experiments demonstrated that BEPD significantly reduced vaginal inflammatory manifestation and the release of proinflammatory cytokines and LDH in mice with VVC caused by C. glabrata. Moreover, it inhibited the Phosphorylation of EGFR, ERK, P38, P65, and C-Fos proteins. The results suggested that although BEPD moderately inhibits the growth and virulence factors of C. glabrata in vitro, it can significantly reduce vaginal inflammation by down-regulating the EGFR/MAPK signaling pathway in mice with VVC infected by C. glabrata.

Competitive interactions and coexistence of sympatric flagship carnivores in Asia.

Understanding the competition and coexistence of flagship carnivores is key to creating strategies for their conservation in the face of global carnivore declines. Although studies exploring the dynamics and competition between tigers (Panthera tigris) and leopards (P. pardus) span decades, there is a lack of understanding regarding the factors that influence their coexistence mechanisms on a broad scale, as well as the drivers determining their exploitative and interference competition. We gathered a comprehensive list of research papers among which 36 papers explored the interspecific interactions between tigers and leopards and tested the influence of biotic and abiotic factors on the coexistence mechanisms along three dimensions using multiple response variables regression models; we also tested the influence of ecological drivers determining the exploitative or interference competition between tigers and leopards. Elevation and ungulate density were the most important predictors in regulating the coexistence mechanisms. Tigers and leopards exhibited more positive relations/higher overlaps as elevation increased in the spatial niche. In addition, they showed a higher dietary overlap in the prey-rich regions. We determined that interference competition between tigers and leopards was less frequently observed in habitats with dense tree cover and homogeneous vegetation structures. Meanwhile, studies with multiple metrics would promote the detection of interference competition. Our study provides new insight into the competitive interactions and coexistence mechanisms of tigers and leopards on a broad scale. Policy-makers and managers should pay more attention to the factors of elevation, prey abundance, and habitat structures for the conservation of tigers and leopards.

Circadian rhythm regulation in the sea cucumber Apostichopus japonicus: Insights into clock gene expression, photoperiod susceptibility, and neurohormone signaling.

Sea cucumber Apostichopus japonicus displays the typical circadian rhythms. This present study investigated the molecular regulation of clock genes, as well as monoamines and melatonin, in multiple tissues of A. japonicus, responding to the photoperiod. In order to determine their pivotal role in circadian rhythms, the crucial clock genes, namely AjClock, AjArnt1, AjCry1, and AjTimeless, were identified and a comprehensive analysis of their expressions across various tissues in adult A. japonicus was conducted, revealing the potential existence of central and peripheral oscillators. Results demonstrated that the tissues of polian vesicle and nerve ring exhibited significant clock gene expression associated with the orchestration of circadian regulation, and that environmental light fluctuations exerted influence on the expression of these clock genes. However, a number of genes, such as AjArnt1 and AjCry1, maintained their circadian rhythmicity even under continuous light conditions. Moreover, we further investigated the circadian patterns of melatonin (MT), serotonin (5-HT), and dopamine (DA) secretion in A. japonicus, data that underscored the tissue-specific regulatory differences and the inherent adaptability to dynamic light environments. Collectively, these findings will provide the molecular mechanisms controlling the circadian rhythm in echinoderms and the candidate tissues playing the role of central oscillators in sea cucumbers.

Ethyl caffeate combined with fluconazole exhibits efficacy against azole-resistant oropharyngeal candidiasis via the EFGR/JNK/c-JUN signaling pathway.

Ethyl caffeate (EC) is a phenylpropanoid compound derived from Elephantopus scaber. In our previous work, EC was investigated to have a strong synergistic antifungal effect against azole-resistant strains of Candida albicans when combined with fluconazole (FLU). However, the protective effect and mechanism of EC + FLU on oropharyngeal candidiasis (OPC) caused by drug-resistant strains of C. albicans have not been investigated. This study aimed to investigate the protective effect and mechanism of EC combined with FLU against C. albicans-resistant strains that lead to OPC. An OPC mouse model revealed that EC + FLU treatment reduced fungal load and massive hyphal invasion of tongue tissues, and ameliorated the integrity of the tongue mucosa. Periodic acid-Schiff staining results showed more structural integrity of the tongue tissues and reduced inflammatory cell infiltration after EC + FLU treatment. Phosphorylation of EGFR (epidermal growth factor receptor) and other proteins in the EFGR/JNK (c-Jun N-terminal kinase)/c-JUN (transcription factor Jun) signaling pathway was significantly downregulated by EC + FLU. EGFR and S100A9 mRNA expression were also reduced. The above results were verified in FaDu cells. ELISA results showed that the concentration of inflammatory factors in the cell supernatant was significantly reduced after EC combined with FLU treatment. Molecular docking revealed that EC exhibited high binding energy to EGFR. In conclusion, EC enhances the susceptibility of azole-resistant C. albicans to FLU, and the underlying mechanism is related to the inhibition of the EGFR/JNK/c-JUN signaling pathway. This result suggests that EC has potential to be developed as an antifungal sensitizer to treat OPC caused by azole-resistant C. albicans.

Evaluation of the Effect and Mechanism of Sanhuang Ointment on MRSA Infection in the Skin and Soft Tissue via Network Pharmacology.

Introduction: Skin and soft tissue infection (SSTI) is a frequently encountered clinical disease, and Sanhuang ointment, a traditional Chinese medicine, is used to treat it. However, the pharmacological effect of Sanhuang ointment on SSTI and its underlying mechanism remains unclear. Here, we investigate the protective effect of Sanhuang ointment on Methicillin-resistant Staphylococcus aureus (MRSA) infection in the skin and soft tissues and the underlying mechanism by network pharmacological analysis, followed by in vivo experimental validation. Methods: Via network pharmacology, the active components and disease targets of Sanhuang ointment were screened and intersected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A rat model of skin and soft tissue infection was established, and pathological features were observed. Large, medium, and small-dose groups (1 g, 0.5 g, and 0.25 g/animal, with the total amount of Vaseline, dispensed 1 g/animal) of Sanhuang ointment were prepared and Mupirocin ointment was used as a positive control (0.5 g/animal, with the total amount of Vaseline, dispensed 1 g/animal). The expressions of key proteins of the IL-17/NF-κB signaling pathway and downstream inflammatory factors were analyzed by histomorphological analysis, enzyme-linked immunosorbent assay, polymerase chain reaction, and Western blotting. Results: In all, 119 active components and 275 target genes of Sanhuang ointment were identified and intersected with MRSA infection-related genes via network pharmacology analysis, and 34 target genes of Sanhuang ointment were found to be involved in skin and soft tissue infections with MRSA. Sanhuang ointment (1 g/mouse) could effectively ameliorate histopathological changes and significantly inhibit the expression of key proteins involved in the IL-17/NF-κB signaling pathway and downstream inflammatory factors (p < 0.05). Conclusion: Sanhuang ointment has a protective effect on MRSA infection and inhibits inflammation by inhibiting the IL-17/NF-κB signaling pathway. Our findings are important for the secondary development and new drug development of Sanhuang ointment.

Assessing mammal population densities in response to urbanization using camera trap distance sampling.

Environmental filtering is deemed to play a predominant role in regulating the abundance and distribution of animals during the urbanization process. However, the current knowledge about the effects of urbanization on the population densities of terrestrial mammals is limited. In this study, we compared two invasive mammals (dogs Canis lupus familiaris and cats Felis silvestris) and three indigenous mammals (Siberian weasels Mustela sibirica, Amur hedgehogs Erinaceus amurensis, and Tolai hares Lepus tolai) in response to urbanization using camera trap distance sampling (CTDS) in the rural-urban landscape of Tianjin, China. We used generalized additive mixed models (GAMMs) to test the specific responses of their densities to levels of urbanization. Invasive dogs (2.63 individuals/km2, 95% CI: 0.91-7.62) exhibited similar density estimations to cats (2.15 individuals/km2, 95% CI: 1.31-3.50). Amur hedgehogs were the most abundant species (6.73 individuals/km2, 95% CI: 3.15-14.38), followed by Tolai hares (2.22 individuals/km2, 95% CI: 0.87-5.68) and Siberian weasels (2.15 individuals/km2, 95% CI: 1.06-4.36). The densities of cats, Siberian weasels, and Amur hedgehogs increased with the level of urbanization. The population densities of dogs and cats were only influenced by urban-related variables, while the densities of Siberian weasels and Amur hedgehogs were influenced by both urban-related variables and nature-related variables. Our findings highlight that the CTDS is a suitable and promising method for wildlife surveys in rural-urban landscapes, and urban wildlife management needs to consider the integrated repercussions of urban- and nature-related factors, especially the critical impacts of green space habitats at finer scales.

Effects of Artificial Light at Night on Fitness-Related Traits of Sea Urchin (Heliocidaris crassispina).

Limited data are available regarding the effects of elevated coastal artificial light at night (ALAN) on intertidal echinoderms. In this study, we investigated the behavioral, morphological, and physiological responses of the sea urchin (Heliocidaris crassispina) after continuous exposure to ALAN at light intensities of 0.1, 300, and 600 Lux for 6 weeks. Our findings revealed that ALAN at 300 Lux substantially reduced food consumption, Lantern weight, and gonadosomatic index (GSI). On the other hand, ALAN at 600 Lux notably prolonged the righting and covering response times and elevated the 5-HIAA/5-HT ratio, while concurrently decreasing food consumption, body weight, Lantern weight, GSI, and Pax6 gene expression. These results indicated that continuous exposure to ALAN could cause an adverse effect on fitness-related traits, including behavioral responses, growth, reproductive performance, and photoreception of sea urchins. The present study provides new insights on the impact of light pollution on echinoderms.